Abstract

Leptin has been consistently associated with tumor pathogenesis and tumor growth. Leptin exerts its physiological action through its specific receptor (Ob-R). We first examined the molecular mechanism underlying this effect and biological significance of inhibition of Ob-R on a panel of EOC cell lines. Because, the role of Leptin and its receptor has not been elucidated in Middle Eastern Epithelial Ovarian Cancer (EOC), we further investigated the potential role and the prognostic significance of Ob-R upregulation and overexpression in Middle Eastern EOC by immunohistochemistry in 156 patient samples using tissue microarray analysis (TMA). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinositol 3\#8217;kinase (PI3K)/AKT signaling pathway. The proliferation and anti-apoptotic effects of leptin were abolished by either inhibition of Ob-R with small interference RNA (siRNA) or inactivation of PI3K/AKT pathway with specific inhibitor, LY294002. In clinical samples, Ob-R immunostaining was detected in 90/152 (59.2%), although no significant clinicopathologic correlation with age, stage, grade or histologic subtype was detected, patient with Ob-R expressing tumor showed a poor progression free survival (p=0.0032). Further, Ob-R expression remained an independent prognostic marker for poor progression free survival in multivariate analysis (p=0.0032) with age, FIGO grade and stage. Our data highlights a major role of Ob-R in Middle Eastern EOC pathogenesis and might provide a link between obesity and EOC in this part of the world. Altogether, data presented here shows that leptin receptor (OB-R) might represent a promising target for anti-cancer drug development in Middle Eastern EOC.